Tiêu đề 4. DETERMINATION OF DOSE AND DOSING INTERVALS.pdf ✅

PHARMD GURU Page 1 DETERMINATION OF DOSE:  The calculation of the starting dose of a drug and dosing interval is based on the objective of delivering a desirable (target) therapeutic level of the drug in the body.  For many drugs, the desirable therapeutic drug levels and pharmacokinetic parameters are available in the literature.  However, the literature in some cases may not yield complete drug information, or some of the information available may be equivocal.  Therefore, the pharmacokineticist must make certain necessary assumptions in accordance with the best pharmacokinetic information available.  For a drug that is given in multiple doses for an extended period of time, the dosage regimen is usually calculated to maintain the average steady-state blood level within the therapeutic range.  The dose can be calculated with Equation given below, which expresses the Cav ∞ in terms of dose (D0), dosing interval (τ), volume of distribution (VD), and the elimina- tion half-life of the drug. F is the fraction of drug absorbed and is equal to 1 for drugs administered intravenously. DETERMINATION OF FREQUENCY OF DRUG ADMINISTRATION:  The drug dose is often related to the frequency of drug administration.  The more frequently a drug is administered, the smaller the dose is needed to obtain the same Cav ∞ .  Thus, a dose of 250 mg every 3 hours can be changed to 500 mg every 6 hours without affecting the average steady-state plasma concentration of the drug.  However, as the dosing intervals get longer, the dose required to maintain the average plasma drug concentration gets correspondingly larger.  When an excessively long dosing interval is chosen, the larger dose may result in peak plasma levels that are above toxic drug concentration and trough plasma concentrations that are below the minimum effective concentration, even though Cav ∞ will remain the same. DETERMINATION OF DOSE AND DOSING INTERVALS
PHARMD GURU Page 2  In general, the dosing interval for most drugs is determined by the elimination half-life.  Drugs such as the penicillin’s, which have relatively low toxicity, may be given at intervals much longer than their elimination half-lives without any toxicity prob- lems.  Drugs having a narrow therapeutic range, such as digoxin and phenytoin, must be given relatively frequently to minimize excessive “peak-and-trough” fluctuations in blood levels.  For example, the common maintenance schedule for digoxin is 0.25 mg/d and the elimination half-life of digoxin is 1.7 days. In contrast, penicillin G is given at 250 mg every 6 hours, while the elimination half-life of penicillin G is 0.75 hour.  Penicillin is given at a dosage interval equal to 8 times its elimination half-life, whereas digoxin is given at a dosing interval only 0.59 times its elimination half- life.  The toxic plasma concentration of penicillin G is over 100 times greater than its effective concentration, whereas digoxin has an effective concentration of 1–2 ng/mL and a toxicity level of 3 ng/mL.  The toxic concentration of digoxin is only 1.5 times effective concentration.  Therefore, a drug with a large therapeutic index (i.e., a large margin of safety) can be given in large doses and at relatively long dosing intervals. DETERMINATION OF BOTH DOSE AND DOSAGE INTERVAL: Both the dose and the dosing interval should be considered in the dosage regimen calculations. For intravenous multiple-dosage regimens, the ratio of may be expressed by: From the above equation, maximum dosage interval, τ, may be calculated that will maintain the serum concentration between desired Cmin ∞ and Cmax ∞ . After the dosage interval is calculated, then a dose may be calculated.
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